Ca1.3 L-type Ca channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na current.

The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na current (I ), a key player in SAN automaticity, is still unknown. Here we show that I and the L-type Ca current (I ) share Ca1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I is activated in the diastolic depolarization range, and displays Na permeability and minimal inactivation and sensitivity to I activators and blockers. Both Ca1.3-mediated I and I were abolished in Ca1.3-deficient (Ca1.3) SAN cells but the Ca1.2-mediated I current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive Ca1.2 channels (Ca1.2), I and Ca1.3-mediated I displayed overlapping sensitivity and concentration-response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that Ca1.3 rather than Ca1.2 underlies I , a considerable fraction of I was resistant to nifedipine inhibition in Ca1.2 SAN cells. These findings identify Ca1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive I Na current in the SAN.